1. Field of the Invention
This invention relates to cationic lipid derivatives of guanidine, their preparation and use, and to pharmaceutical compositions using such derivatives.
2. Background Information
A number of lipid based materials, such as liposomes, have been used effectively as carriers in several pharmaceutical and biological situations to introduce biologically active substances such as drugs, radiotherapeutic agents, enzymes, viruses, nucleic acids,(e.g., plasmids, DNA and RNA constructs, transcription factors and other cellular vectors) into cultured cell lines and animals. For example, several lipid encapsulated drugs such as daunorubicin (DaunoXome.TM.) and amphotericin B (Abelcet.TM., Ambisome.TM., Amphotec.TM.) have recently been approved by the Food and Drug Administration(FDA) or are the subject of NDA filings under current FDA review.
In this vein, much effort has been directed towards developing lipid mediated methods for efficiently and efficaciously delivering genetic material directly to a biological cell. For example, gene therapy techniques alleviate disease states by transfecting target cells of a patient with nucleic acid constructs which are capable of affecting the processes of gene replication, transcription and translation in a therapeutically desirable manner. Typically, these nucleic acid constructs are high molecular weight, polyanionic molecules for which carrier-mediated delivery is usually required for successful transfection of cells either in vivo, ex vivo or in vitro. See, for example, U.S. Pat. No. 5,264,618, which describes a number of techniques for using lipid based carriers and such pharmaceutical compositions in clinical settings. Such transfection methods are also used in developing novel cell lines and animals which produce commercially significant proteins.
Several lipid carriers have recently been disclosed for plasmid delivery. See, U.S. Pat. Nos. 4,897,355; 4,946,787; 5,049,386; 5,366,737; 5,545,412 to Felgner et al., U.S. Pat. Nos. 5,264,618; 5,283,185 (to Epand et al. describing DC-chol); 5,334,761; PCT Publications WO 95/14381; WO 96/01840; WO 96/1841; and WO 96/18372 and Felgner et al., Methods in Enzymology, 5, 67-75 (1993). Although the compounds described in the above references facilitate the entry of biologically active substances into cells, it is still desirable to develop additional lipid carriers which provide higher uptake efficiencies, greater specificity and reduced toxicity. This invention fulfills this and related needs.